CBD and Euromed’s milk thistle extract both investigated in COVID-19 battle

17 Jul 2020 --- Silibinin sourced from Euromed SA’s milk thistle extract and cannabidiol (CBD) are the latest ingredients to come under the microscope in the fight against the COVID-19 crisis. Silibinin, a key component of flavonoid silymarin, will be used in a clinical trial called SilCOVID19 for oncohematological patients diagnosed with COVID-19. Meanwhile, US researchers have early evidence that CBD may help reduce the cytokine storm and excessive lung inflammation that is killing many patients with COVID-19. Notably, they used a new model that could also open the door for further safe research of the novel coronavirus.

“The SilCOVID19 study is a phase II, randomized, controlled, open-label, clinical trial. There will be a first safety cohort of ten patients to confirm that dose used in the trial is safe. Then there will be a randomized phase with 41 patients per arm (control and experimental),” Dr. Joaquim Bosch-Barrera, Principle Investigator of the SilCovid19 clinical trial, tells NutritionInsight. 

The study will then run until April 2021 or until all 92 patients have been included in the study, which will be conducted at the Catalan Institute of Oncology in Catalonia, Spain. It will test the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome (ARDS) in oncology patients hospitalized with COVID-19. 

Euromed is contributing to this academic study with an unrestricted research grant donation to allow the start of the clinical project. “We are now looking for additional economic support from public and private society to grant the success of the rest of the clinical trial. This is an old and safe drug, having been approved in Spain since 1974 for liver disorders. A complete treatment of one patient costs around €18 (US$21). Due to its cost and good safety profile, it could be an important molecule for this global pandemic. Before it can be used, we have to demonstrate that it is useful in a clinical trial,” adds Bosch-Barrera.

Milk thistle seed extracts, of which silibinin is an active ingredient, have validated benefits for liver health.Detailing the investigation
In this study, silibinin from milk thistle extract that is processed at Euromed SA will be administered to patients through the drug Legalon. The patients will each receive 1050 mg per day of silibinin supplementation for 7 to 14 days. The primary endpoint is the proportion of patients that do not die of respiratory failure or do not need mechanical ventilatory support. Other secondary endpoints are overall survival rate at 30 days, safety profile and serologic biomarkers.

“The SilCOVID19 study was designed during the first wave of COVID-19 in Spain between March and May 20 and, despite a very fast review of the protocol, until the beginning of June, we didn’t have all the regulatory approvals for the initiation of the study. Currently, the most important limitation for the study is that there are no oncologic patients with COVID-19 in our region,” details Bosch-Barrera.

However, he notes that it is very probable that new cases will appear in the near future, which will continue until an active vaccine is developed. After the safety cohort, the study will be opened to other centers, which the researchers hope will facilitate the inclusion of all the patients required for the study. 

“Whereas numerous pharma and biotech companies and academic institutions are racing to develop vaccine candidates for effective COVID-19 prevention, the rapid global spread of COVID-19 has stressed the need for new therapeutics. We present a comprehensive review of the evidence-based research into the multi-faceted capacity of silibinin to target the host cytokine storm and the virus lifecycle to clinically manage COVID-19. We acknowledge that measurement of the therapeutic efficacy requires randomized trials of silibinin therapy,” write the authors of a study published in the Journal of Clinical Medicine, which details the background for SilCOVID19. 

Bosch-Barrera has already published several previous studies showing the antitumor ability of silibinin in cancer patients. Meanwhile, in his Journal of Clinical Medicine paper, he states (along with other co-authors) that their present work aims to provide a basis for the design of new silibinin-based antiviral therapeutics or supportive care approaches against the COVID-19. 

Bosch-Barrera details the connection between cancer and worse COVID-19 outcomes, noting that those with cancer are at five times higher risk of mortality than the general population. “For this reason, it is important to find a potential treatment with a good safety profile and potential benefit for this specific population. However, the mechanism of action of silibinin is not specific for cancer patients, and if the study is positive, it could also be a potential COVID-19 treatment for the general population.”

Milk thistle seed extracts, of which silibinin is an active ingredient, have validated benefits for liver health. According to Euromed, the extracts are generally used both preventively and curatively to protect the organ from toxins, including alcohol and heavy metals. 

Eyeing the evidenceThere are multiple aspects of the evidence that silibinin could be used against COVID-19. (Source: Journal of Clinical Medicine) 
The researchers detail the clinical-molecular evidence of silibinin as a possible treatment for COVID-19 is in multiple parts. Firstly, it could have potential as an immunomodulator of the “cytokine storm,” which is one of the key mechanisms in the poor prognosis of patients COVID-19 with acute respiratory distress syndrome. This mechanism would depend on the STAT3 protein, a molecular target of silibinin that the same researchers had already described in patients with brain metastases. Thus, this first level of action would take place in the patient.

Next, the researchers propose that silibinin could work as an antiviral. This is presented in a comprehensive computational analysis of a new mechanism of silibinin against RNA polymerase of SARS-CoV-2, which is the main component of the virus replication machinery. This computational study, developed in collaboration with Dr. José Antonio Encinar of the University of Elche, predicts a silibinin pharmacological behavior similar to that of Remdesivir. Euromed notes that Remdesivir recently became the first drug approved by the European Agency for Drug (EMA) against COVID-19. This second level of action would take place in the virus itself.

At least one way CBD is thought to calm the immune response is because it looks similar to endocannabinoids.Investigating CBD with a new model
Across the Atlantic, researchers from the Dental College of Georgia and Medical College of Georgia (MCG) propose that CBD could help patients showing signs of respiratory distress avoid extreme interventions like mechanical ventilation, as well as death from ARDS.

“Our laboratory studies indicate pure CBD can help the lungs recover from the overwhelming inflammation, or cytokine storm, caused by the COVID-19 virus, and restore healthier oxygen levels in the body,” says co-author Dr. Jack Yu, Physician-Scientist and Chief of Pediatric Plastic Surgery at MCG.

The researchers used a safe and relatively inexpensive model to duplicate the lung damage caused by ARDS. The model takes advantage of the large, unique genetic structure of the novel coronavirus and could also open more doors for studying COVID-19 and similar virus-induced conditions. Currently, US capabilities of safely managing the highly contagious virus are limited to just a handful of labs. 

The study saw the model produce classic symptoms of ARDS before CBD significantly downregulated classic indicators of the excess, like inflammation-promoting cytokines. It also improved oxygen levels in the blood and enabled the lungs to recover from the structural damage. The researchers state that both clinical symptoms and physical lung changes resulting from ARDS were reversed with CBD treatment.

At least one way CBD is thought to calm the immune response is because it looks similar to endocannabinoids. These make up a natural cell signaling system in the body believed to be involved in a wide variety of functions from sleep to reproduction to inflammation and immune response. CB1 and CB2, the main receptors for this system, are found extensively throughout the body, including the brain and respiratory system.

“While understanding the workings of the natural endocannabinoid system is still very much a work in progress, it’s thought that one way CBD works to reduce seizures, for example, is indirectly through the large number of CB1 receptors in the brain,” says Yu.

The researchers now flag that more work, including clinical trials to determine optimal dosage and timing, is needed before CBD becomes part of the treatment for COVID-19. A variety of other ingredients have also surfaced in the fight against the pandemic, including fucoidan, pomegranate, probiotics, and ashwagandha and propolis.

To keep readers informed of these rapid developments, NutritionInsight is updating its daily news feed for the coronavirus-related information and insights you need to guide your business through this challenging period.

By Katherine Durrell